2,5-Inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-PGF1 amides

ABSTRACT

The present invention provides 2,5-inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-PGF 1  amides. These compounds are useful for a wide variety of pharmacological and therapeutical purposes, e.g., as antithrombotic agents.

CROSS REFERENCE TO RELATED APPLICATION

This application is a division of Ser. No. 62,443, filed July 31, 1979,now U.S. Pat. No. 4,312,810, which is a continuation-in-part of Ser. No.962,845, filed Nov. 22, 1978, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to novel prostacyclin analogs andintermediates for their production. Most particularly, the presentinvention provides 2,5-inter-o-phenylene-3,4-dinor-6,9α-epoxy-6β-PGF₁amides. The preparation and use of the novel compounds described hereinis incorporated here by reference from U.S. Pat. No. 4,281,113.

SUMMARY OF THE INVENTION

The present invention particularly provides a prostacyclin analog offormula VI ##STR1##

wherein R₈ is hydrogen, hydroxy, or hydroxymethyl;

wherein Y₁ is

(1) trans--CH═CH--,

(2) cis--CH═CH--,

(3) --CH₂ CH₂, or

(4) --C.tbd.C--,

wherein M₁ is α-R₅ :β-OH or α-OH:β-R₅, wherein R₅ is hydrogen or alkylwith one to 4 carbon atoms, inclusive,

wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture of α-R₃ :β-R₄ andα-R₄ :β-R₃, wherein R₃ and R₄ are hydrogen, methyl, or fluoro, being thesame or different, with the proviso that one of R₃ and R₄ is fluoro onlywhen the other is hydrogen or fluoro;

wherein R₇ is

(1) --(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive;

(2) phenoxy;

(3) phenoxy substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl,alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbonatoms, inclusive, with the proviso that not more than two substituentsare other than alkyl;

(4) phenyl;

(5) phenyl substituted by one, 2 or 3 chloro, fluoro, trifluoromethyl,alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3 carbonatoms, inclusive, with the proviso that not more than two substituentsare other than alkyl;

(6) phenylmethyl, phenylethyl, or phenylpropyl; or

(7) phenylmethyl, phenylethyl, or phenylpropyl substituted by one, 2 or3 chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms,inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with theproviso that not more than two substituents are other than alkyl; withthe proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ andR₄ are hydrogen or methyl, being the same or different;

wherein L₄ is

(1) amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are

(a) hydrogen;

(b) alkyl of one to 12 carbon atoms, inclusive;

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive;

(d) aralkyl of 7 to 12 atoms, inclusive;

(e) phenyl;

(f) phenyl substituted with one, 2 or 3 chloro, alkyl of one to 3 carbonatoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to 4 carbonatoms, inclusive, or nitro;

(g) carboxyalkyl of 2 to 5 carbon atoms, inclusive;

(h) carbamoylalkyl of 2 to 5 carbon atoms, inclusive;

(i) cyanoalkyl of 2 to 5 carbon atoms, inclusive;

(j) acetylalkyl of 3 to 6 carbon atoms, inclusive;

(k) benzoylalkyl of 7 to 11 carbon atoms, inclusive;

(l) benzoylalkyl substituted by one, 2 or 3 chloro, alkyl of one to 3carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbon atoms,inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms, inclusive,or nitro;

(m) pyridyl;

(n) pyridyl substituted by one, 2 or 3 chloro, alkyl of one to 3 carbonatoms, inclusive, or alkoxy of one to 3 carbon atoms, inclusive;

(o) pyridylalkyl of 6 to 9 carbon atoms, inclusive;

(p) pyridylalkyl substituted by one, 2 or 3 chloro, alkyl of one to 3carbon atoms, inclusive, hydroxy or alkoxy of one to 3 carbon atoms,inclusive;

(q) hydroxyalkyl of one to 4 carbon atoms, inclusive;

(r) dihydroxyalkyl of one to 4 carbon atoms; or

(s) trihydroxyalkyl of one to 4 carbon atoms; with the further provisothat not more than one of R₂₁ and R₂₂ is other than hydrogen or alkyl;

(2) cycloamino selected from the group consisting of

(a) pyrrolidino,

(b) piperidino,

(c) morpholino,

(d) piperazino,

(e) hexamethyleneimino,

(f) pyrrolino,

(g) 3,4-didehydropiperidinyl, or

(h) pyrrolidino, piperidino, morpholino, piperazino, hexamethyleneimino,pyrrolino, or 3,4-didehydropiperidinyl substituted by one or 2 alkyl ofone to 12 carbon atoms, inclusive;

(3) carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogenor alkyl of one to 4 carbon atoms, inclusive, and R₂₁ is other thanhydrogen, but otherwise as defined above; or

(4) sulfonylamino of the formula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ areas defined in (3).

The novel prostaglandin analogs are useful for a variety ofprostacyclin-like pharmacological purposes, particularly and especiallyas inhibitors of platelet aggregation in vivo and in vitro. Thus, theseprostacyclin analogs are useful for a variety of pharmacological andtherapeutical purposes, e.g., as antithrombotic agents.

We claim:
 1. A prostacyclin analog of formula VI ##STR2## wherein R₈ ishydrogen, hydroxy, or hydroxymethyl; wherein Y₁ is(1) trans--CH═CH--,(2) cis--CH═CH--, (3) --CH₂ CH₂, or (4) --C.tbd.C--, wherein M₁ is α-R₅:β-OH or α-OH:βR₅, wherein R₅ is hydrogen or alkyl with one to 4 carbonatoms, inclusive, wherein L₁ is α-R₃ :β-R₄, α-R₄ :β-R₃, or a mixture ofα-R₃ :β-R₄ and α-R₄ :β-R₃, wherein R₃ and R₄ are hydrogen, methyl, orfluoro, being the same or different, with the proviso that one of R₃ andR₄ is fluoro only when the other is hydrogen or fluoro; wherein R₇ is(1)--(CH₂)_(m) --CH₃, wherein m is an integer from one to 5, inclusive; (2)phenoxy; (3) phenoxy substituted by one, 2 or 3 chloro, fluoro,trifluoromethyl, alkyl of one to 3 carbon atoms, inclusive, or alkoxy ofone to 3 carbon atoms, inclusive, with the proviso that not more thantwo substituents are other than alkyl; (4) phenyl; (5) phenylsubstituted by one, 2 or 3 chloro, fluoro, trifluoromethyl, alkyl of oneto 3 carbon atoms, inclusive, or alkoxy of one to 3 carbon atoms,inclusive, with the proviso that not more than two substituents areother than alkyl; (6) phenylmethyl, phenylethyl, or phenylpropyl; or (7)phenylmethyl, phenylethyl, or phenylpropyl substituted by one, 2 or 3chloro, fluoro, trifluoromethyl, alkyl of one to 3 carbon atoms,inclusive, or alkoxy of one to 3 carbon atoms, inclusive, with theproviso that not more than two substituents are other than alkyl; withthe proviso that R₇ is phenoxy or substituted phenoxy, only when R₃ andR₄ are hydrogen or methyl, being the same or different; wherein L₄ is(1)amino of the formula --NR₂₁ R₂₂, wherein R₂₁ and R₂₂ are(a) hydrogen;(b) alkyl of one to 12 carbon atoms, inclusive;(c) cycloalkyl of 3 to 10carbon atoms, inclusive; (d) aralkyl of 7 to 12 carbon atoms, inclusive;(e) phenyl; (f) phenyl substituted with one, 2 or 3 chloro, alkyl of oneto 3 carbon atoms, inclusive, hydroxy, carboxy, alkoxycarbonyl of one to4 carbn atoms, inclusive, or nitro;(g) carboxyalkyl of 2 to 5 carbonatoms, inclusive; (h) carbamoylalkyl of 2 to 5 carbon atoms, inclusive;(i) cyanoalkyl of 2 to 5 carbon atoms, inclusive; (j) acetylalkyl of 3to 6 carbon atoms, inclusive; (k) benzoylalkyl of 7 to 11 carbon atoms,inclusive; (l) benzoylalkyl substituted by one, 2 or 3 chloro, alkyl ofone to 3 carbon atoms, inclusive, hydroxy, alkoxy of one to 3 carbonatoms, inclusive, carboxy, alkoxycarbonyl of one to 4 carbon atoms,inclusive, or nitro; (m) pyridyl; (n) pyridyl substituted by one, 2 or 3chloro, alkyl of one to 3 carbon atoms, inclusive, or alkoxy of one to 3carbon atoms, inclusive; (o) pyridylalkyl of 6 to 9 carbon atoms,inclusive; (p) pyridylalkyl substituted by one, 2 or 3 chloro, alkyl ofone to 3 carbon atoms, inclusive, hydroxy or alkoxy of one to 3 carbonatoms, inclusive; (q) hydroxyalkyl of one to 4 carbon atoms, inclusive;(r) dihydroxyalkyl of one to 4 carbon atoms; or (s) trihydroxyalkyl ofone to 4 carbon atoms; with the further proviso that not more than oneof R₂₁ and R₂₂ is other than hydrogen or alkyl; (2) cycloamino selectedfrom the group consisting of(a) pyrrolidino, (b) piperidino, (c)morpholino, (d) piperazino, (e) hexamethyleneimino, (f) pyrrolino, (g)3,4-didehydropiperidinyl, or (h) pyrrolidino, piperidino, morpholino,piperazino, hexamethyleneimino, pyrrolino, or 3,4-didehydropiperidinylsubstituted by one or 2 alkyl of one to 12 carbon atoms, inclusive; (3)carbonylamino of the formula --NR₂₃ COR₂₁, wherein R₂₃ is hydrogen oralkyl of one to 4 carbon atoms, inclusive, and R₂₁ is other thanhydrogen, but otherwise as defined above; or (4) sulfonylamino of theformula --NR₂₃ SO₂ R₂₁, wherein R₂₁ and R₂₃ are as defined in (3).